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Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration

Cited 530 time in Web of Science Cited 572 time in Scopus
Authors
Choi, Se-Young; Saura, Carlos A; Beglopoulos, Vassilios; Malkani, Seema; Zhang, Dawei; Shankaranarayana rao, B.S; Chattarji, Sumantra; Kelleher, Raymond J; Kandel, Eric R; Duf, Karen; Kirkwood, Alfredo; Shen, Jie
Issue Date
2004-04
Publisher
Cell Press
Citation
NEURON. 42, 23-36. (2004)
Abstract
Mutations in presenilins are the major cause of familial Alzheimer's disease, but the pathogenic mechanism by which presenilin mutations cause memory loss and neurodegeneration remains unclear. Here we demonstrate that conditional double knockout mice lacking both presenilins in the postnatal forebrain exhibit impairments in hippocampal memory and synaptic plasticity. These deficits are associated with specific reductions in NMDA receptor-mediated responses and synaptic levels of NMDA receptors and αCaMKII. Furthermore, loss of presenilins causes reduced expression of CBP and CREB/CBP target genes, such as c-fos and BDNF. With increasing age, mutant mice develop striking neurodegeneration of the cerebral cortex and worsening impairments of memory and synaptic function. Neurodegeneration is accompanied by increased levels of the Cdk5 activator p25 and hyperphosphorylated tau. These results define essential roles and molecular targets of presenilins in synaptic plasticity, learning and memory, and neuronal survival in the adult cerebral cortex.
ISSN
0896-6273
Language
English
URI
http://hdl.handle.net/10371/62645
DOI
https://doi.org/10.1016/S0896-6273(04)00182-5
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College of Dentistry/School of Dentistry (치과대학/치의학대학원)Dept. of Dentistry (치의학과)Journal Papers (저널논문_치의학과)
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